A multi-species synthesis of physiological mechanisms in drought-induced tree mortality

Widespread tree mortality associated with drought 92 has been observed on all forested continents, and global change is expected to exacerbate vegetation vulnerability. Forest mortality has implications for future biosphere-atmosphere interactions of carbon, water, and energy balance, and is poorly represented in dynamic vegetation models. Reducing uncertainty requires improved mortality projections founded on robust physiological processes. However, the proposed mechanisms of drought-induced mortality, including hydraulic failure and carbon starvation, are unresolved. A growing number of empirical studies have investigated these mechanisms, but data have not been consistently analyzed across species and biomes using a standardized physiological framework. Here we show that xylem hydraulic failure was ubiquitous across multiple tree taxa at drought induced mortality. All species assessed had 60% or higher loss of xylem hydraulic conductivity, consistent with proposed theoretical and modelled survival thresholds. We found diverse responses in non-structural carbohydrate reserves at mortality, indicating that evidence supporting carbon starvation was not universal. Reduced non-structural carbohydrates were more common for gymnosperms than angiosperms, associated with xylem hydraulic vulnerability, and may have a role in reducing hydraulic function. Our finding that hydraulic failure at drought-induced mortality was persistent across species indicates that substantial improvement in vegetation modelling can be achieved using thresholds in hydraulic function

A multi-species synthesis of physiological mechanisms in drought-induced tree mortality

Widespread tree mortality associated with drought 92 has been observed on all forested continents, and global change is expected to exacerbate vegetation vulnerability. Forest mortality has implications for future biosphere-atmosphere interactions of carbon, water, and energy balance, and is poorly represented in dynamic vegetation models. Reducing uncertainty requires improved mortality projections founded on robust physiological processes. However, the proposed mechanisms of drought-induced mortality, including hydraulic failure and carbon starvation, are unresolved. A growing number of empirical studies have investigated these mechanisms, but data have not been consistently analyzed across species and biomes using a standardized physiological framework. Here we show that xylem hydraulic failure was ubiquitous across multiple tree taxa at drought induced mortality. All species assessed had 60% or higher loss of xylem hydraulic conductivity, consistent with proposed theoretical and modelled survival thresholds. We found diverse responses in non-structural carbohydrate reserves at mortality, indicating that evidence supporting carbon starvation was not universal. Reduced non-structural carbohydrates were more common for gymnosperms than angiosperms, associated with xylem hydraulic vulnerability, and may have a role in reducing hydraulic function. Our finding that hydraulic failure at drought-induced mortality was persistent across species indicates that substantial improvement in vegetation modelling can be achieved using thresholds in hydraulic function

Global transpiration data from sap flow measurements: The SAPFLUXNET database

Plant transpiration links physiological responses of vegetation to water supply and demand with hydrological, energy, and carbon budgets at the land-atmosphere interface. However, despite being the main land evaporative flux at the global scale, transpiration and its response to environmental drivers are currently not well constrained by observations. Here we introduce the first global compilation of whole-plant transpiration data from sap flow measurements (SAPFLUXNET, https://sapfluxnet.creaf.cat/, last access: 8 June 2021). We harmonized and quality-controlled individual datasets supplied by contributors worldwide in a semi-automatic data workflow implemented in the R programming language. Datasets include sub-daily time series of sap flow and hydrometeorological drivers for one or more growing seasons, as well as metadata on the stand characteristics, plant attributes, and technical details of the measurements. SAPFLUXNET contains 202 globally distributed datasets with sap flow time series for 2714 plants, mostly trees, of 174 species. SAPFLUXNET has a broad bioclimatic coverage, with woodland/shrubland and temperate forest biomes especially well represented (80% of the datasets). The measurements cover a wide variety of stand structural characteristics and plant sizes. The datasets encompass the period between 1995 and 2018, with 50% of the datasets being at least 3 years long. Accompanying radiation and vapour pressure deficit data are available for most of the datasets, while on-site soil water content is available for 56% of the datasets. Many datasets contain data for species that make up 90% or more of the total stand basal area, allowing the estimation of stand transpiration in diverse ecological settings. SAPFLUXNET adds to existing plant trait datasets, ecosystem flux networks, and remote sensing products to help increase our understanding of plant water use, plant responses to drought, and ecohydrological processes. SAPFLUXNET version 0.1.5 is freely available from the Zenodo repository (10.5281/zenodo.3971689; Poyatos et al., 2020a). The "sapfluxnetr"R package-designed to access, visualize, and process SAPFLUXNET data-is available from CRAN. © 2021 Rafael Poyatos et al.This research was supported by the Minis-terio de Economía y Competitividad (grant no. CGL2014-55883-JIN), the Ministerio de Ciencia e Innovación (grant no. RTI2018-095297-J-I00), the Ministerio de Ciencia e Innovación (grant no. CAS16/00207), the Agència de Gestió d’Ajuts Universitaris i de Recerca (grant no. SGR1001), the Alexander von Humboldt-Stiftung (Humboldt Research Fellowship for Experienced Researchers (RP)), and the Institució Catalana de Recerca i Estudis Avançats (Academia Award (JMV)). Víctor Flo was supported by the doctoral fellowship FPU15/03939 (MECD, Spain)

Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease.

ObjectiveTo determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD).MethodsThis NIH/National Institute on Aging-funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (ClinicalTrials.gov, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2.ResultsOf 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months.ConclusionThis interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials.Classification of evidenceThis study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months

Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease

OBJECTIVE: To determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: This NIH/National Institute on Aging–funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (ClinicalTrials.gov, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2. RESULTS: Of 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months. CONCLUSION: This interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months

Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology

The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules.This study was initiated by the generosity of Harry Bubb through Cure Alzheimer’s Fund CAF-50997 (F.M.L.). Additional support was from Alzheimer’s Association NIRG-15-363477 (D.B.V.), AARF-16-440760 (S.F.) and NIRG-394284 (I.M.G.), The Larry Hillblom Foundation 2013-A-016-FEL (D.B.V.) and 2016-A-016-FEL (A.C.M.), the National Institute of Health (NIH) NIH/NIA/NINDS AG027544 (F.M.L.), AG00538 (F.M.L.), AG54884 (F.M.L.), OD010420 (F.M.L.), U54 AG054349 (F.M.L., A.J.T.), AG049562 (C.S.) NS083801 (K.N.G.) and AG056768 (K.N.G.), BrightFocus Foundation grant A2015535S (F.M.L.), by Minister of Science and Innovation grant PID2019-108911RA-100 (D.B.V.), Beatriz Galindo program BAGAL18/00052 (D.B.V.) and Institute of Health Carlos III (ISCiii) grant PI18/01557 (A.G.) co-financed by FEDER funds from European Union, by American federation of aging research-AFAR young investigator award and UC Irvine startup funds (V.S.) and UCI MIND pilot project (D.B.V.). The UCI-ADRC is funded by NIH/NIA Grant P50 AG16573 (F.M.L.). Genetically modified hAβ-KI mice were generated by the UCI Transgenic Mouse Facility, a shared resource funded in part by the Chao Family Comprehensive Cancer Center Support Grant (P30CA062203) from the National Cancer Institute. We thank Drs. Malcolm Leissring and Rodrigo Medeiros for critically reading the manuscript.Ye

Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology.

The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules